Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development
Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development
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DOI：
10.1210/jc.2007-1101
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发表时间：
2007-10-01
影响因子：
5.8
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Hachiya, Rumi;Ohashi, Yuko;Ogawa, Yoshihiro
内容：利钠肽受体- B（啮齿类动物中的NPR- B，GC- B;基因名称NPR 2）是鸟苷酸环化酶偶联受体，介导C型利钠肽的作用。人NPR- B纯合突变引起肢端中肢发育不良，Maroteaux型（OMIM 602875），一种常染色体隐性骨骼发育不良。NPR- B有一个细胞内激酶同源结构域（KHD），它没有激酶活性，其在体内的功能意义目前还不清楚.Objective：We examined the functional significance of a novel NPR- B KHD mutation in human.Patients and Methods：A 28-year- old Japanese male presented with marked short statement（118.5 cm，- 9.3 SD）.他的四肢中段和远段明显缩短。他的父母身材相对较矮，身高z分数分别为-2.75和-0.98（他的父亲和母亲）。对该家族的NPR 2基因编码区进行直接测序。通过饱和结合试验和cGMP测定研究突变体受体活性。结果：在患者及其父母的纯合子和杂合子状态下，我们分别在NPR- B基因KHD中发现了一个新的错义突变L 658 F。该突变赋予了正常的C型利钠肽结合亲和力，但没有明显的配体诱导的cGMP产生.此外，L 658 F突变体以剂量依赖性方式损害野生型NPR- B介导的cGMP产生，表明L 658 F杂合子中发现的矮小可能是由其显性负效应引起的。结论：本研究首次提供了NPR- B完整KHD对骨骼发育至关重要的证据。
Context: Natriuretic peptide receptor- B ( NPR- B, GC- B in rodents; gene name NPR2) is a guanylyl cyclase- coupled receptor that mediates the effect of C- type natriuretic peptide. Homozygous mutations in human NPR- B cause acromesomelic dysplasia, type Maroteaux ( OMIM 602875), an autosomal recessive skeletal dysplasia. NPR- B has an intracellular kinase homology domain ( KHD), which has no kinase activity, and its functional significance in vivo is currently unknown.Objective: We examined the functional significance of a novel NPR- B KHD mutation in humans.Patients and Methods: A 28- yr- old Japanese male presented with marked short stature ( 118.5 cm, - 9.3 SD). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z- scores of - 2.75 and - 0.98 ( his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and wild type allele was investigated by the titration experiments.Results: We identified a novel missense mutation L658F in KHD of NPR- B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for C- type natriuretic peptide but no discernible ligand- induced cGMP production. Furthermore, L658F mutant impaired wild- type NPR- B- mediated cGMP production in a dose- dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant- negative effect.Conclusions: This study provides the first evidence that intact KHD of NPR- B is essential for skeletal development.